Impact of Chemotherapy on Bladder Function in Children

化疗对儿童膀胱功能的影响

• 批准号: 10213024
• 负责人: Nicholas G Cost
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-08 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213024
• 关键词: Address; Adenosine Triphosphate; Adult; Affect; Area; Award; Biological Markers; Bladder; Bladder Dysfunction; Brain-Derived Neurotrophic Factor; Cancer Survivor; Cancer Survivorship; Cardiac; Caregivers; Caring; Chemotherapy-Oncologic Procedure; Child; Childhood; Clinical; Clinical Data; Communities; Complex; Data; Disease; Doxorubicin; Education; Ensure; Epidemiology; Exhibits; Exposure to; Failure; Fellowship; Foundations; Functional disorder; Funding; Future; Gender; Goals; Grant; Health; Heart failure; Institution; Investigation; Kidney; Knowledge; Laboratories; Late Effects; Life; Malignant Childhood Neoplasm; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Mus; Muscle; Nerve Growth Factors; Neurogenic Bladder; Oncologist; Outcome; Patients; Pediatric Oncology; Peripheral Nervous System Diseases; Physiological; Physiology; Population; Prevalence; Price; Productivity; Proteome; Proteomics; Publishing; Quality of life; Research; Research Personnel; Risk; Scientist; Second Primary Cancers; Societies; Surgeon; Surveys; Survivors; Symptoms; System; Time; Training; United States; Urologic Oncology; Urologist; Urology; Vincristine; Vision; Work; base; cancer care; cancer therapy; career; chemotherapy; childhood cancer survivor; cost; experience; follow-up; gonad function; health related quality of life; individual patient; innovation; mouse model; neurotoxicity; prevent; psychosocial; relating to nervous system; side effect; skills; success; survivorship; trend; urinary; urologic

PROJECT SUMMARY/ABSTRACT This K23 proposal will provide Nicholas G. Cost, MD with the protected time, mentorship, training, and experience to become an independent surgeon-scientist. Dr. Cost is a board-certified urologist with a unique practice focused on pediatric urologic oncology developed after fellowship training in both urologic oncology and pediatric urology. His long-term vision is to minimize the impact of pediatric cancer care on long-term urologic outcomes. Specifically, he is focused on studying the impact of chemotherapy on bladder function. This involves studying the epidemiology of bladder dysfunction (BD) in childhood cancer survivors and investigating alterations in bladder physiology induced by chemotherapy. This will mature into studying mechanisms behind this pathophysiology and identifying biomarkers of chemotherapy-induced BD. Skills that he will acquire during the award, include: 1) didactic and “hands on” education in epidemiology, 2) advanced laboratory skills in the study of bladder physiology, and 3) investigation into urinary proteomics and biomarkers. This grant proposes to objectively describe the prevalence and extent of chemotherapy-induced pediatric BD, as well as explain the mechanisms of dysfunction in order to prevent chemotherapy-induced BD. While chemotherapy is the foundation for treating childhood cancer, these therapies are known to have a variety of deleterious side effects. There is much known about their most common side effects, but there has been no investigation into how chemotherapy impacts bladder function. In connecting chemotherapy to potential BD, there are two widely used agents in pediatric oncology, Vincristine (VCR) and Doxorubicin (DOX), which are known to cause peripheral neuropathy (VCR) and myotoxicity (DOX). Such neurotoxicity and myotoxicity could rationally induce BD. This grant proposes to address this gap in knowledge with three specific aims: 1) To evaluate the symptoms of BD in children treated with VCR and/or DOX; 2) To determine the mechanisms underlying BD after VCR and/or DOX using a murine model; 3) To evaluate the urinary proteome, as well as levels of known urinary biomarkers of BD, in children exposed to VCR and/or DOX. The first aim will leverage a large pediatric cancer survivorship population at Dr. Cost's institution. The second and third aim will be supported by Dr. Cost's mentors who have a strong track record of innovative research in bladder physiology. The proposed work has high potential to make a significant clinical impact. It will be the first description of this clinical phenomenon and represents the necessary initial steps in a career-long investigation into understanding and preventing chemotherapy-induced pediatric BD. Based on Dr. Cost's initial work, past productivity, and strong mentorship team, the proposed work is realistic and feasible within the award period and will provide Dr. Cost the skills necessary to compete for future R01 or equivalent funding. This award comes at an ideal time in Dr. Cost's career to provide the necessary support to enable him to become a successful independent surgeon-scientist.

项目概要/摘要 该 K23 提案将为医学博士 Nicholas G. Cost 提供受保护的时间、指导、培训和 Cost 博士是一位经过委员会认证的泌尿科医生，拥有成为一名独立外科医生兼科学家的经验。 在泌尿肿瘤学进修培训后开发的侧重于儿科泌尿肿瘤学的实践 他的长期愿景是尽量减少儿科癌症护理对长期的影响。 具体来说，他专注于研究化疗对膀胱功能的影响。 这涉及研究儿童癌症幸存者膀胱功能障碍（BD）的流行病学和 化疗引起的膀胱生理学改变的研究将逐渐成熟。 这种病理生理学背后的机制和识别化疗引起的 BD 的生物标志物。 他将在获奖期间获得包括：1）流行病学方面的教学和“实践”教育，2）高级 膀胱生理学研究的实验室技能，以及 3) 尿蛋白质组学和生物标志物的研究。 该赠款旨在客观地描述化疗引起的儿科疾病的患病率和程度 BD，以及解释功能障碍的机制，以预防化疗引起的 BD。 化疗是治疗儿童癌症的基础，已知这些疗法具有多种作用 人们对它们最常见的副作用有很多了解，但还没有发现任何副作用。 研究化疗如何影响膀胱功能 将化疗与潜在的 BD 联系起来。 有两种在儿科肿瘤学中广泛使用的药物，长春新碱（VCR）和阿霉素（DOX），它们是 已知会引起周围神经病（VCR）和肌肉毒性（DOX）。 此项拨款旨在通过三个具体目标来解决这一知识差距：1） 评估接受 VCR 和/或 DOX 治疗的儿童的 BD 症状 2) 确定机制； 使用小鼠模型进行 VCR 和/或 DOX 治疗后潜在的 BD；3) 评估尿液蛋白质组以及 暴露于 VCR 和/或 DOX 的儿童中已知的 BD 尿液生物标志物水平第一个目标将利用 Cost 博士所在机构的第二个和第三个目标是扩大儿童癌症幸存者群体。 得到了 Cost 博士导师的支持，他们在膀胱生理学创新研究方面拥有良好的记录。 拟议的工作具有产生重大临床影响的巨大潜力，这将是第一个描述。 这种临床现象代表了长期研究中必要的初始步骤 了解和预防化疗引起的儿科 BD 基于 Cost 博士过去的初步工作。 生产力和强大的导师团队，所提出的工作在奖励期内是现实可行的 并将为 Cost 博士提供竞争未来 R01 或同等资金所需的技能。 科斯特博士的职业生涯正处于一个理想的时期，为他提供必要的支持，使他能够成为一名 成功的独立外科医生兼科学家。